Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial

Abstract

We report a randomized prospective phase 3 study (CLL7), designed to evaluate the efficacy of fludarabine, cyclophosphamide, and rituximab (FCR) in patients with an early-stage high-risk chronic lymphocytic leukemia (CLL). Eight hundred patients with untreated-stage Binet A disease were enrolled as intent-to-treat population and assessed for four prognostic markers: lymphocyte doubling time <12 months, serum thymidine kinase >10 U/L, unmutated IGHV genes, and unfavorable cytogenetics (del(11q)/del(17p)/trisomy 12). Two hundred and one patients with ≥2 risk features were classified as high-risk CLL and 1:1 randomized to receive either immediate therapy with 6xFCR (Hi-FCR, 100 patients), or to be observed according to standard of care (Hi-W&W, 101 patients). The overall response rate after early FCR was 92.7%. Common adverse events were hematological toxicities and infections (61.0%/41.5% of patients, respectively). After median observation time of 55.6 (0-99.2) months, event-free survival was significantly prolonged in Hi-FCR compared with Hi-W&W patients (median not reached vs. 18.5 months, p < 0.001). There was no significant overall survival benefit for high-risk patients receiving early FCR therapy (5-year OS 82.9% in Hi-FCR vs. 79.9% in Hi-W&W, p = 0.864). In conclusion, although FCR is efficient to induce remissions in the Binet A high-risk CLL, our data do not provide evidence that alters the current standard of care "watch and wait" for these patients.

Trial registration: ClinicalTrials.gov NCT00275054.

Conflict of interest statement

CDH received research funding and travel support from Roche. PL and KF received travel support from Roche. JB received consulting honoraria and travel support from Roche. MH and CMW report advisory board membership for Roche, and obtained research funding, consulting honoraria, and speaker’s honoraria from Roche. SB reports consulting fees, honoraria, and research funding from Roche. SS declares advisory board membership, consulting honoraria, speaker’s honoraria, research grants and travel support from Roche. All other authors declare no competing financial interests.

Figures

Fig. 1. Trial flow diagram illustrating patient assessment and allocation within the CLL7 study.

AIHA autoimmune hemolytic anemia, EFS event-free survival, FCR fludarabine, cyclophosphamide, and rituximab, PFS progression-free survival, OS overall survival, W&W watch and wait.

Fig. 2. Event-free survival (EFS) and overall survival (OS) according to risk stratification/randomization (ITT).

a EFS from stratification. b OS from stratification. Hi-FCR high-risk CLL treated with early FCR, Hi-W&W high-risk CLL under observation, and Lo-W&W low-risk CLL under observation (watch and wait).

Fig. 3. Event-free survival (EFS) and overall survival (OS) according to MRD status in peripheral blood.

a EFS from MRD landmark (final response assessment/MRD evaluation). b OS from MRD landmark (final response assessment/MRD evaluation). MRD minimal residual disease. For this calculation, the MRD status at the final restaging was considered. MRD negative < 10−4; positive ≥ 10−4 detected CLL cells per leukocytes, according to MRD-flow cytometry. For MRD-results from bone marrow please refer to Supplementary Figs. 1 and 2.

Fig. 4. Time to (re)treatment (TTT) according to risk stratification/randomization and treatment status per protocol.

a Time to first treatment (TTT) in Hi- and Lo-risk patient categories, considering also Hi-FCR patients, who had withdrawn their consent for early FCR after trial inclusion. b Time to re-treatment in Hi-FCR patients, who actually underwent early FCR therapy according to the protocol (SP safety population).